This invention relates to an antimicrobial compound useful as a drug for humans, animals or fishes or an antimicrobial preservative and an antimicrobial agent or preparation containing the same.
Since the discovery of Norfloxacin, synthetic quinolone antimicrobial agents have been improved in antimicrobial activity and pharmacokinetics, and many compounds have been launched for clinical use as a chemotherapeutic agent effective on all most all systemic infectious diseases.
However, bacteria having low sensitivity to the synthetic quinolone antimicrobial agents have recently been increasing in the clinical field. For example, bacteria which have not only resistance to drugs other than synthetic quinolone antimicrobial agents but low sensitivity to synthetic quinolone antimicrobial agents, as exemplified by Staphylococcus aureaus insensitive to xcex2-lactam antibiotics (MRSA), have been increasing. Therefore, more effective drugs have been keenly demanded in the field of clinics.
Further, it has been revealed that synthetic quinolone antimicrobial agents tend to induce convulsion in a combined use with a non-steroid antiinflammatory agent or involve side effects such as phototoxicity. Therefore, development of safer synthetic quinolone antimicrobial agents has been sought.
In the light of these circumstances, the inventors have conducted extensive investigation for the purpose of providing excellent compounds fulfilling the above demands. As a result, they have found that tricyclic amine derivatives represented by formula (I) shown below and their salts and hydrates thereof have high antimicrobial activity broadly on Gram positive bacteria and Gram negative bacteria, exhibiting potent antimicrobial activity particularly on quinolone-resistant bacteria including MRSA, and also show satisfactory pharmacokinetics and safety.
The present invention relates to a compound represented by formula (I) shown below and its salt and their hydrates. 
wherein R1 and R2 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkoxyl group having 1 to 6 carbon atoms;
R3 represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms, in which the alkyl group may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R4 and R5 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the alkyl group may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R6 and R7 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
X1 represents an oxygen atom, a sulfur atom, a partial structure: 
(wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2) or a partial structure: 
(wherein R10 represents a hydrogen atom, a formyl group, an acyl group having 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbon atoms);
n represents an integer 1 or 2; and
Q represents a partial structure represented by formula: 
(wherein R11 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an alkoxyl group having 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms;
R12 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms;
R11 and R12 may be taken together with part of the mother skeleton to which they are bonded to form a cyclic structure that may have a sulfur atom as a ring-constituting atom and an alkyl group having 1 to 6 carbon atoms as a substituent;
R13 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms;
X2 represents a halogen atom or a hydrogen atom;
A1 represents a nitrogen atom or a partial structure represented by formula (II): 
wherein X3 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms; and X3 and R11 may be taken together with part of the mother skeleton to which they are bonded to form a cyclic structure that may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring-constituting atom and an alkyl group having 1 to 6 carbon atoms as a substituent;
A2 and A3 each represents a nitrogen atom or a carbon atoms provided that A2, A3, and the carbon atom to which they are bonded form a partial structure:
 greater than Cxe2x95x90C(A1xe2x95x90)xe2x80x94N(R11)xe2x80x94
or a partial structure:
 greater than Nxe2x80x94C(A1xe2x95x90)xe2x95x90C(R11)xe2x80x94
wherein  greater than  indicates the carbon atom or the nitrogen atom has two bonds (hereinafter the same); and
Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group).
The present invention also relates to:
(1) the compound of formula (I), wherein Q is a structure represented by formula: 
or a structure represented by formula: 
a salt or hydrate thereof, and a hydrate of the salt;
(2) the compound of formula (I), wherein Q is a structure represented by formula: 
a salt or hydrate thereof, and a hydrate of the salt;
(3) the compound of formula (I), wherein Q is a 9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]benzoxazin-6-carboxylic acid-10-yl group of formula: 
a salt or hydrate thereof, and a hydrate of the salt;
(4) the compound of formula (I), wherein Q is a 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinolin-3-carboxylic acid-7-yl group of formula: 
a salt or hydrate thereof, and a hydrate of the salt;
(5) the compound of formula (I), wherein Q is a 6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinolin-3-carboxylic acid-7-yl group of formula: 
a salt or hydrate thereof, and a hydrate of the salt;
(6) the compound of formula (I), wherein Q is a 5-amino-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinolin-3-carboxylic acid-7-yl group of formula: 
a salt or hydrate thereof, and a hydrate of the salt;
(7) the compound of formula (I), wherein X1 is a partial structure represented by formula: 
wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2, a salt or a hydrate thereof, and a hydrate of the salt;
(8) the compound of formula (I), wherein R8 and R9 are each a hydrogen atom, and m is 1, a salt or hydrate thereof, and a hydrate of the salt;
(9) the compound of formula (I), wherein n is 1, a salt or hydrate thereof, and a hydrate of the salt;
(10) the compound of formula (I), wherein n is 1, and X1 is a partial structure represented by formula: 
wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and m represents an integer 1 or 2, a salt or hydrate thereof, and a hydrate of the salt;
(11) the above compound in which R8 and R9 are each a hydrogen atom, a salt or hydrate thereof, and a hydrate of the salt;
(12) the above compound in which m is 1, a salt or hydrate thereof, and a hydrate of the salt;
(13) the above compound in which R8 and R9 are each a hydrogen atom, and m is 1, a salt and hydrate thereof, and a hydrate of the salt;
(14) the compound of formula (I) which is a stereochemically pure compound, a salt or hydrate thereof, and a hydrate of the salt;
(15) the above compound in which R11 is a cyclopropyl group having a halogen atom as a substituent, a salt or hydrate thereof, and a hydrate of the salt;
(16) the above compound in which the cyclopropyl group having a halogen atom as a substituent is a 1,2-cis-halogenocyclopropyl group, a salt or hydrate thereof, and a hydrate of the salt;
(17) the above compound in which the cyclopropyl group having a halogen atom as a substituent is a stereochemically pure substituent, a salt or hydrate thereof, and a hydrate of the salt;
(18) the above compound in which the cyclopropyl group having a halogen atom as a substituent is a (1R,2S)-2-halogenocyclopropyl group, a salt or hydrate thereof, and a hydrate of the salt;
(19) the above compound in which the halogen atom of the cyclopropyl group having a halogen atom as a substituent is a fluorine atom, a salt or hydrate thereof, and a hydrate of the salt;
(20) the above compound in which each of R3, R4, R5, R6, and R7 is a hydrogen atom, a salt or hydrate thereof, and a hydrate of the salt;
(21) the above compound in which n is 1, a salt or hydrate thereof, and a hydrate of the salt;
(22) the compound of formula (I), wherein X1 is a partial structure represented by formula: 
wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m is an integer 1 or 2, a salt or hydrate thereof, and a hydrate of the salt;
(23) the above compound in which R8 and R9 are each a hydrogen atom, a salt or hydrate thereof, and a hydrate of the salt;
(24) the above compound in which R8 and R9 are each a hydrogen atom; and m is 1, a salt or hydrate thereof, and a hydrate of the salt;
(25) the above compound in which R1 and R2 are each a hydrogen atom, a salt or hydrate thereof, and a hydrate of the salt;
(26) a drug characterized by containing the above-described compound, a salt or hydrate thereof, or a hydrate of the salt as an active ingredient;
(27) an antimicrobial agent characterized by containing the above-described compound, a salt or hydrate thereof, or a hydrate of the salt as an active ingredient;
(28) a treating agent for an infectious disease characterized by containing the above-described compound, a salt or hydrate thereof, or a hydrate of the salt as an active ingredient;
(29) a method for treating a disease characterized by administering the above-described compound, a salt or hydrate thereof or a hydrate of the salt;
(30) a method for treating an infectious disease characterized by administering the above-described compound, a salt or hydrate thereof or a hydrate of the salt;
(31) a method for producing a drug characterized by compounding the above-described compound, a salt or hydrate thereof or a hydrate of the salt as an active ingredient;
(32) a method for producing an antimicrobial agent characterized by compounding the above-described compound, a salt or hydrate thereof or a hydrate of the salt as an active ingredient;
(33) a method for producing a treating agent for an infectious disease characterized by compounding the above-described compound, a salt or hydrate thereof or a hydrate of the salt as an active ingredient;
(34) use of the above-described compound, a salt or hydrate thereof or a hydrate of the salt for production of a drug;
(35) use of the above-described compound, a salt or hydrate thereof or a hydrate of the salt for production of an antimicrobial agent;
(36) use of the above-described compound, a salt or hydrate thereof or a hydrate of the salt for production of a treating agent for an infectious disease;
(37) a compound represented by formula: 
wherein R111 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a protective group for amino group;
R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
in which the alkyl group as R111 or R2 may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkoxyl group having 1 to 6 carbon atoms;
R3 represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms, in which the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R4 and R5 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms, in which the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R6 and R7 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
X1 represents an oxygen atom, a sulfur atom, a partial structure: 
(wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2) or a partial structure: 
(wherein R10 represents a hydrogen atom, a formyl group, an acyl group having 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbon atoms);
n represents an integer 1 or 2; and
Qxe2x80x2 represents a protective group for amino group, a salt or hydrate thereof, and a hydrate of the salt;
(38) the above compound in which the protective group for amino group is a protective group selected from the group consisting of a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted aralkyloxycarbonyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, and a silyl group, a salt or hydrate thereof, and a hydrate of the salt;
(39) the above compound in which the protective group for amino group is a protective group selected from the group consisting of a t-butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyl group, a benzoyl group, a t-butyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a triphenylmethyl group, a methoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group, a 2,2,2-trichloroethoxymethyl group, a trimethylsilyl group, an isopropyldimethylsilyl group, a t-butyldimethylsilyl group, a tribenzylsilyl group, and a t-butyldiphenylsilyl group, a salt or hydrate thereof, and a hydrate of the salt;
(40) the above compound in which R111 and Qxe2x80x2 are not the same protective groups, a salt or hydrate thereof, and a hydrate of the salt;
(41) the above compound in which n is 1, a salt or hydrate thereof, and a hydrate of the salt;
(42) the above compound in which each of R2, R3, R4, R5, R6, and R7 is a hydrogen atom, a salt or hydrate thereof, and a hydrate of the salt;
(43) the above compound in which X1 is a partial structure of formula: 
wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2, a salt or hydrate thereof, and a hydrate of the salt;
(44) the above compound in which m is 1, a salt or hydrate thereof, and a hydrate of the salt;
(45) a compound represented by formula: 
wherein R111 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a protective group for amino group;
R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
in which the alkyl group as R111 or R2 may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkoxyl group having 1 to 6 carbon atoms;
R3 represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms, in which the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R4 and R5 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms, in which the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R6 and R7 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
X1 represents an oxygen atom, a sulfur atom, a partial structure: 
(wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2) or a partial structure: 
(wherein R10 represents a hydrogen atom, a formyl group, an acyl group having 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbon atoms); and
n represents an integer 1 or 2, a salt or hydrate thereof, and a hydrate of the salt;
(46) the above compound in which the protective group for amino group is a protective group selected from the group consisting of a substituted or unsubstituted alkoxycarbonyl group, a substituted or unsubstituted aralkyloxycarbonyl group, a substituted or unsubstituted acyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aralkyl group, and a silyl group, a salt or hydrate thereof, and a hydrate of the salt;
(47) the above compound in which the protective group for amino group is a protective group selected from the group consisting of a t-butoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyl group, a benzoyl group, a t-butyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, a triphenylmethyl group, a methoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group, a 2,2,2-trichloroethoxymethyl group, a trimethylsilyl group, an isopropyldimethylsilyl group, a t-butyldimethylsilyl group, a tribenzylsilyl group, and a t-butyldiphenylsilyl group, a salt or hydrate thereof, and a hydrate of the salt;
(48) the above compound in which n is 1, a salt or hydrate thereof, and a hydrate of the salt;
(49) the above compound in which each of R2, R3, R4, R5, R6, and R7 is a hydrogen atom, a salt or hydrate thereof, and a hydrate of the salt;
(50) the above compound in which X1 is apartial structure of formula: 
wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2, a salt or hydrate thereof, and a hydrate of the salt;
(51) the above compound in which m is 1, a salt or hydrate thereof, and a hydrate of the salt;
(52) a process for preparing a quinolone compound characterized by comprising removing Qxe2x80x2 from a compound of the following formula, a salt or hydrate thereof, or a hydrate of the salt: 
wherein R111 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a protective group for amino group;
R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
in which the alkyl group as R111 or R2 may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkoxyl group having 1 to 6 carbon atoms;
R3 represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms, in which the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R4 and R5 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms, in which the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R6 and R7 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
X1 represents an oxygen atom, a sulfur atom, a partial structure: 
(wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2) or a partial structure: 
(wherein R10 represents a hydrogen atom, a formyl group, an acyl group having 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbon atoms);
n represents an integer 1 or 2; and
Qxe2x80x2 represents a protective group for amino group, and reacting the resulting compound as obtained or, if desired, as isolated and purified with a compound represented by formula (III): 
wherein X2 represents a halogen atom or a hydrogen atom;
X4 represents a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms;
Y1 represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, or a boron-containing group represented by formula (IV):
xe2x80x94B(Y11)Y12xe2x80x83xe2x80x83(IV)
(wherein Y11 and Y12 each represents a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms);
R11 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms;
R12 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms;
R12 and R11 may be taken together with part of the mother skeleton to which they are bonded to form a cyclic structure that may contain a sulfur atom as a ring-constituting atom and an alkyl group having to 6 carbon atoms as a substituent;
R13 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms; and
A1 represents a nitrogen atom or a partial structure represented by formula (II): 
(wherein X3 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms; and X3 and R11 may be taken together with part of the mother skeleton to which they are bonded to form a cyclic structure that may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring-constituting atom and an alkyl group having 1 to 6 carbon atoms as a substituent), or a compound represented by formula (V): 
wherein X2, X4, R11, R12, R13, A1, and Y are as defined above, in the presence of a base, and if desired removing a protective group;
(53) a process for preparing a quinolone compound characterized by comprising reacting a compound represented by formula (VI), a salt or hydrate thereof, or a hydrate of the salt: 
wherein R111 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a protective group for amino group;
R2 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
in which the alkyl group as R111 or R2 may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkoxyl group having 1 to 6 carbon atoms;
R3 represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms, in which the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R4 and R5 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms, in which the alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms;
R6 and R7 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms;
X1 represents an oxygen atom, a sulfur atom, a partial structure: 
(wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2) or a partial structure: 
(wherein R10 represents a hydrogen atom, a formyl group, an acyl group having 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbon atoms); and
n represents an integer 1 or 2, with a compound represented by formula (III): 
wherein X2 represents a halogen atom or a hydrogen atom;
X4 represents a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group or a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms;
Y1 represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms, a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group, or a boron-containing group represented by formula (IV):
xe2x80x83xe2x80x94B(Y11)Y12xe2x80x83xe2x80x83(IV)
(wherein Y11 and Y12 each represents a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms);
R11 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms;
R12 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms;
R12 and R11 may be taken together with part of the mother skeleton to which they are bonded to form a cyclic structure that may contain a sulfur atom as a ring-constituting atom and an alkyl group having 1 to 6 carbon atoms as a substituent;
R13 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms; and
A1 represents a nitrogen atom or a partial structure represented by formula (II): 
(wherein X3 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5 carbon atoms; and X3 and R11 may be taken together with part of the mother skeleton to which they are bonded to form a cyclic structure that may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring-constituting atom and an alkyl group having 1 to 6 carbon atoms as a substituent), or a compound represented by formula (V): 
wherein X2, X4, R11, R12, R13, A1, and Y are as defined above, in the presence of a base, and if desired removing a protective group; and the like.
The compound represented by formula (I) according to the present invention is described with reference to the substituents thereof.
Substituents R1 and R2 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms which may be substituted with one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbon atoms, and an alkoxyl group having 1 to 6 carbon atoms.
The alkyl group can be a straight-chain or branched alkyl group having 1 to 6 carbon atoms and preferably includes a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.
Where the alkyl group has a hydroxyl group as a substituent, the alkyl group having 1 to 6 carbon atoms can be either straight or branched, and the hydroxyl group is preferably on the terminal carbon atom of the alkyl group. The hydroxyl-substituted alkyl group preferably contains up to 3 carbon atoms and preferably includes a hydroxymethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, and a 3-hydroxypropyl group.
Where the alkyl group has a halogen atom as a substituent, the alkyl group having 1 to 6 carbon atoms can be either straight or branched, and the halogen atom is preferably a fluorine atom. The number of fluorine substitution is any of from mono-substitution up to perfluoro-substitution. Examples of the halogen-substituted alkyl group are a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a 2,2,2-trifluoroethyl group.
Where the alkyl group has an alkylthio group as a substituent, the alkyl group having 1 to 6 carbon atoms can be either straight or branched, and the alkylthio group can be a straight-chain or branched group having 1 to 6 carbon atoms. The alkylthio-substituted alkyl group preferably includes an alkylthiomethyl group, an alkylthioethyl group, and an alkylthiopropyl group, in which thealkylthio group preferablyhasup to 3 carbonatoms. Still preferred are a methylthiomethyl group, an ethylthiomethyl group, and a methylthioethyl group.
Where the alkyl group has an alkoxyl group as a substituent, the alkyl group having 1 to 6 carbon atoms can be either straight or branched, and the alkoxyl group can be a straight-chain or branched group having 1 to 6 carbon atoms. The alkoxy-substituted alkyl group preferably includes an alkoxymethyl group, an alkoxyethyl group, and an alkoxypropyl group, in which the alkoxyl group preferably contains up to 3 carbon atoms. Still preferred are a methoxymethyl group, an ethoxymethyl group, and a methoxyethyl group.
Substituent R3 represents a hydrogen atom, a hydroxyl group, a halogen atom, a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms. The alkyl group may have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom, and an alkoxyl group having 1 to 6 carbon atoms.
The halogen atom is preferably a fluorine atom or a chlorine atom.
The alkyl group having 1 to 6 carbon atoms can be either straight or branched and preferably includes a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.
The alkoxyl group having 1 to 6 carbon atoms can be either straight or branched and preferably includes a methoxyl group and an ethoxy group.
The alkylthio group having 1 to 6 carbon atoms can be either straight or branched and preferably includes a methylthio group and an ethylthio group.
Where a hydroxyl group is on the alkyl group having 1 to 6 carbon atoms as a substituent, the alkyl group can be either straight or branched, and the hydroxyl group is preferably on the terminal carbon atom of the alkyl group. The hydroxyl-substituted alkyl group having 1 to 6 carbon atoms preferably includes a hydroxymethyl group, a 2-hydroxyethyl group, and a 3-hydroxypropyl group.
The halogen atom of the halogen-substituted alkyl group is preferably a fluorine atom or a chlorine atom, with a fluorine atom being particularly preferred. The alkyl group can be either straight or branched.
Either alkyl moiety of the alkoxy-substituted alkyl group having 1 to 6 carbon atoms can be straight or branched. An alkoxymethyl group or an alkoxyethyl group is preferred. Still preferred are a methoxymethyl group, an ethoxymethyl group, and a 2-methoxyethyl group.
Substituents R4 and R5 each independently represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the alkyl group can have one or more substituents selected from the group consisting of a hydroxyl group, a halogen atom and an alkoxyl group having 1 to 6 carbon atoms.
The halogen atom is preferably a fluorine atom or a chlorine atom.
The alkyl group having 1 to 6 carbon atoms can be either straight or branched and preferably includes a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.
The alkoxyl group having 1 to 6 carbon atoms can be either straight or branched and preferably includes a methoxyl group and an ethoxy group.
The hydroxyl-substituted alkyl group having 1 to 6 carbon atoms can be either straight or branched, and the hydroxyl group is preferably on the terminal carbon atom of the alkyl group. The hydroxyl-substituted alkyl group having 1 to 6 carbon atoms preferably includes a hydroxymethyl group, a 2-hydroxyethyl group, and a 3-hydroxypropyl group.
The halogen atom of the halogen-substituted alkyl group is preferably a fluorine atom or a chlorine atom, with a fluorine atom being particularly preferred. The alkyl group can be either straight or branched.
Either alkyl moiety of the alkoxy-substituted alkyl group having 1 to 6 carbon atoms can be straight or branched. An alkoxymethyl group or an alkoxyethyl group is preferred. Still preferred are a methoxymethyl group, an ethoxymethyl group, and a 2-methoxyethyl group.
Substituents R6 and R7 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. The alkyl group having 1 to 6 carbon atoms can be straight or branched and preferably includes a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.
X1 represents an oxygen atom, a sulfur atom, a partial structure: 
wherein R8 and R9 each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; and m represents an integer 1 or 2, or a partial structure: 
wherein R10 represents a hydrogen atom, a formyl group, an acyl group having 2 to 5 carbon atoms or an alkyl group having 1 to 6 carbon atoms.
X1 is preferably the partial structure: 
wherein
R8, R9, and m are as defined above.
R8 and R9 are preferably a hydrogen atom, and m is preferably 1.
n is preferably an integer 1 or 2, still preferably 1.
Q represents a partial structure represented by formula: 
In the above formula, A2 and A3 each represents a nitrogen atom or a carbon atoms provided that A2, A3 and the carbon atom to which they are bonded are linked to form a partial structure:
 greater than Cxe2x95x90C(A1xe2x95x90)xe2x80x94N(R11)xe2x80x94
or a partial structure:
 greater than Nxe2x80x94C(A1xe2x95x90)xe2x95x90C(R11)xe2x80x94
Q preferably represents a condensed heterocyclic structure represented by formula: 
Substituent R11 represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an alkoxyl group having 1 to 6 carbon atoms or an alkylamino group having 1 to 6 carbon atoms.
The alkyl group having 1 to 6 carbon atoms is particularly preferably an ethyl group. The alkenyl group having 2 to 6 carbon atoms preferably includes a vinyl group and a 1-isopropenyl group. The halogenoalkyl group having 1 to 6 carbon atoms is preferably a 2-fluoroethyl group. The cycloalkyl group is preferably a cyclopropyl group. The substituent on the cycloalkyl group is preferably a halogen atom, which is preferably a fluorine atom.
The substituted or unsubstituted aryl group includes a phenyl group which may have 1 to 3 substituents selected from the group consisting of a halogen atom (e.g., fluorine, chlorine, and bromine), a hydroxyl group, an amino group, a nitro group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, etc. The substituted or unsubstituted aryl group preferably includes a phenyl group, a 2-fluorophenyl group, a 4-fluorophenyl group, 2,4-difluorophenyl group, and a 2-fluoro-4-hydroxyphenyl group.
The heteroaryl group is a substituent derived from a 5-membered or 6-membered aromatic heterocyclic compound containing at least one hetero atom selected from a nitrogen atom, an oxygen atom and a sulfur atom and includes a pyridyl group and a pyrimidyl group. The substituents on the heteroaryl group preferably include an alkyl group and a halogen atom.
The alkoxyl group having 1 to 6 carbon atoms is preferably a methoxyl group. The alkylamino group having 1 to 6 carbon atoms is preferably a methylamino group.
Substituent R11 is preferably a cycloalkyl group or a halogenocycloalkyl group, still preferably a cyclopropyl group or a 2-halogenocyclopropyl group, in which the halogen atom is preferably a fluorine atom.
Substituent R12 represents a hydrogen atom or an alkylthio group having 1 to 6 carbon atoms, or R11 and R12 may be taken together with part of the mother skeleton (that is, the nitrogen atom to which R11 is bonded and the carbon atom to which R12 is bonded) to form a hydrocarbon ring structure. The ring formed may contain a sulfur atom in its ring. The ring may be substituted with an alkyl group having 1 to 6 carbon atoms. The ring can be a 4- to 6-membered ring and may be saturated, partially saturated or unsaturated. The condensed ring structure thus formed includes the following structures. 
Substituent X2 represents a halogen atom or a hydrogen atom. The halogen atom is preferably a fluorine atom. X2 is preferably a fluorine atom or a hydrogen atom.
Substituent R13 represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group may have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms.
The alkyl group having 1 to 6 carbon atoms can be straight or branched and preferably includes a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. The alkenyl group having 2 to 6 carbon atoms can be straight or branched and preferably includes a vinyl group. The alkynyl group having 2 to 6 carbon atoms can be straight or branched and preferably includes an ethynyl group. The halogen of the halogenomethyl group is preferably a fluorine atom. The halogenomethyl group can have 1 to 3 halogen atoms. The alkoxyl group can have 1 to 6 carbon atoms and is preferably a methoxyl group.
Substituent R13 is preferably a hydrogen atom, an alkyl group or an amino group, with a methyl group or an unsubstituted amino group being still preferred.
Where substituent R13 is an amino group, a hydroxyl group or a thiol group, it may be protected with a commonly employed protective group.
Specific examples of the protective group include (substituted) alkoxycarbonyl groups, e.g., a t-butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group; (substituted) aralkyloxycarbonyl groups, e.g., a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl group; (substituted) acyl groups, e.g., an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyl group, and a benzoyl group; (substituted) alkyl groups or (substituted) aralkyl groups, e.g., a t-butyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, and a triphenylmethyl group; (substituted) ether groups, e.g, a methoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group, and a 2,2,2-trichloroethoxymethyl group; and (alkyl- and/or aralkyl)-substituted silyl groups, e.g., a trimethylsilyl group, an isopropyldimethylsilyl group, a t-butyldimethylsilyl group, a tribenzylsilyl group, and a t-butyldiphenylsilyl group. The term xe2x80x9csubstitutedxe2x80x9d in parentheses as used above means substituted or unsubstituted (hereinafter the same). The compounds having the thus protected substituent are particularly useful as an intermediate for synthesis.
Where A1 is a partial structure of formula (II): 
X3 represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl group having 1 to 6 carbon atoms, in which the amino group can have one or two substituents selected from the group consisting of a formyl group, an alkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5 carbon atoms.
The alkyl group can be a straight-chain or branched alkyl group having 1 to 6 carbon atoms and preferably includes a methyl group, an ethyl group, an n-propyl group, and an isopropyl group. The alkenyl group can be a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and preferably includes a vinyl group. The alkynyl group can be a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and preferably includes an ethynyl group. The halogenomethyl group can contain 1 to 3 halogen atoms, and the halogen atom thereof is preferably a fluorine atom. The alkoxyl group has 1 to 6 carbon atoms and is preferably a methoxyl group. The halogenomethoxyl group can have 1 to 3 halogen atoms, and the halogen atom thereof is preferably a fluorine atom.
Of these substituents an alkyl group and an alkoxyl group are preferred. A methyl group and an ethyl group are still preferred. They are preferred particularly where Q is a partial structure of formula: 
X3 and R11 may be taken together with part of the mother skeleton (that is, so as to include the carbon atom to which X3 is bonded and the nitrogen atom to which R11 is bonded) to form a hydrocarbon ring structure. The ring has a size of from 4- to 6-membered rings and may be saturated, partially saturated or unsaturated. The ring may contain an oxygen atom, a nitrogen atom or a sulfur atom as a ring-constituting atom. The ring may also have an alkyl group having 1 to 6 carbon atoms as a substituent. The condensed ring structure thus formed includes the following structures. 
Of the condensed rings preferred is a 2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-6-carboxylic acid-10-yl group, especially the 3(S)-methyl form thereof.
Q preferably represents a partial structure of formula: 
Q still preferably represents the above structure in which A1 is the partial structure of formula (II).
Where Q is the partial structure shown above in which A1 is the partial structure of formula (II), R13 and X3 are preferably selected to make such a combination that R12 is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms, and X3 is an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group or a hydrogen atom. In a still preferred combination, R13 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X3 is a methyl group, a methoxyl group, a difluoromethoxyl group or a hydrogen atom. A particularly preferred combination is that R13 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X3 is a methyl group or a methoxyl group.
In the above cases, X2 is preferably a fluorine atom.
Where X2 and X3 are each a halogen atom, X2 is preferably a fluorine atom, and X3 is preferably a fluorine atom or a chlorine atom.
Where Q is a partial structure represented by formula: 
and A1 is the partial structure of formula (II), R13 and X3 are preferably selected to make such a combination that R12 is an amino group, a hydrogen atom, a hydroxyl group or an alkyl group having 1 to 6 carbon atoms, and X3 is an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogenomethoxyl group or a hydrogen atom. In a still preferred combination, R13 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X3 is a methyl group, a methoxyl group, a fluorine atom, a chlorine atom, a difluoromethoxyl group or a hydrogen atom. A particularly preferred combination is that R13 is an amino group, a hydrogen atom, a hydroxyl group or a methyl group, and X3 is a methyl group or a methoxyl group.
Where X2 and X3 are each a halogen atom, X2 is preferably a fluorine atom, and X3 is preferably a fluorine atom or a chlorine atom.
The halogenocyclopropyl group as R11 will hereinafter be described.
The substituent halogen atom includes a fluorine atom and a chlorine atom, with a fluorine atom being preferred.
It is particularly preferred that the halogen atom and the pyridonecarboxylic acid moiety be in a cis-configuration with respect to the cyclopropane ring.
The cis-2-halogenocyclopropyl moiety as R11 makes a pair of antipodes by itself, each of which was observed to exhibit potent antimicrobial activity and high safety.
The compound of the present invention is characterized by having the substituent represented by the following structure: 
In this substituent, it is usual that the substituents xe2x80x94N(R1)R2 and R3 are in a cis-configuration, so are the substituents R4 and R5. Therefore there are 4 isomers with respect to the condensed rings on which these substituents are.
Where the compound of formula (I) of the invention has such a structure that produces diastereomers, it is desirable to administer a compound comprising a pure diastereomer in administration to humans or animals. The language xe2x80x9ca compound comprising a pure diastereomerxe2x80x9d as used herein is construed as including not only a compound containing no other diastereomers at all but a compound containing other diastereomers to such an extent that the compound is regarded to be chemically pure. In other words, it is construed as meaning that other diastereomers may exist to some extent as long as the existence gives no substantial influence on physical constants or physiological activities.
The language xe2x80x9cstereochemically purexe2x80x9d as used herein is intended to mean that a compound comprises only one of its stereoisomers ascribed to its asymmetric carbon atom. The latitude of the term xe2x80x9cpurexe2x80x9d in xe2x80x9cpure diastereomerxe2x80x9d also applies here.
The pyridonecarboxylic acid derivative of the present invention may have either a free form or a form of an acid addition salt or a carboxylic acid salt. Acid addition salts include inorganic acid salts, such as a hydrochloride, a sulfate, a nitrate, a hydrobromide, a hydroiodide, and a phosphate; and organic acid salts, such as an acetate, a metanesulfonate, a benzenesulfonate, a toluenesulfonate, a citrate, a maleate, a fumarate, and a lactate.
The carboxylic acid salts include inorganic salts and organic salts, such as alkali metal salts, e.g., a lithium salt, a sodium salt, and a potassium salt; alkaline earth metal salts, e.g., a magnesium salt and a calcium salt; an ammonium salt; a triethylamine salt, an N-methylglucamine salt, and a tris-(hydroxymethyl)aminomethane salt.
The free pyridonecarboxylic acid derivatives, acid addition salts thereof, and carboxylic acid salts thereof may be present as a hydrate.
On the other hand, quinolone derivatives with the carboxylic acid moiety thereof having an ester form are useful as an intermediate for synthesis or a pro-drug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters, and phenyl esters are useful as intermediates for synthesis.
Esters which can be used as pro-drugs are those which are susceptible to an in vivo cleavage to form a free carboxylic acid, including an acetoxymethyl ester, a pivaloyloxymethyl ester, an ethoxycarbonyl ester, a choline ester, a dimethylaminoethyl ester, a 5-indanyl ester, a phthalidinyl ester, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, and oxoalkyl esters, such as a 3-acetoxy-2-oxobutyl ester.
The compound of formula (I) can be prepared through various processes. A preferred process comprises reacting a compound represented by formula (III): 
wherein X4 represents a group functioning as a leaving group, such as a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms, and the like; Y1 has the same meaning as Y in formula (I) or represents a boron-containing group represented by formula (IV):
xe2x80x94B(Y11)Y12xe2x80x83xe2x80x83(IV)
(wherein Y11 and Y12 each represent a fluorine atom or an alkylcarbonyloxy group having 2 to 4 carbon atoms); and R11, R12, R13, A1, and X2 are as defined in formula (I), or a compound represented by formula (V): 
wherein X4 represents a group functioning as a leaving group, such as a fluorine atom, a chlorine atom, a bromine atom, a substituted or unsubstituted phenylsulfonyl group, a substituted or unsubstituted alkylsulfonyl group having 1 to 3 carbon atoms, and the like; and R11, R12, R13, A1, X2, and Y are as defined in formula (I), with a compound represented by formula (VI): 
wherein R111 has the same meaning as R1 in formula (I) or represents a protective group for amino group; and R2, R3, R4, R5, R6, R7, X1, and n are as defined in formula (I), or an acid addition salt thereof.
The reaction is carried out with or without a solvent. The solvent which can be used in the reaction is not limited as long as it is inert under the reaction conditions. Suitable solvents include dimethyl sulfoxide, pyridine, acetonitrile, ethanol, chloroform, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, water, and 3-methoxybutanol, and mixtures thereof.
It is advantageous to conduct the reaction in the presence of an acid acceptor, such as an inorganic base (e.g., an alkali metal or alkaline earth metal carbonate or hydrogencarbonate) or an organic base (e.g., triethylamine, pyridine or 1,8-diazabicycloundecene). The reaction is usually performed at room temperature to 200xc2x0 C., preferably 25 to 150xc2x0 C., for 0.5 to 48 hours. The reaction usually completes in about 0.5 to 2 hours.
Any protective group generally used in the art can be used as a protective group for amino group. Examples of useful protective groups include (substituted) alkoxycarbonyl groups, e.g., a t-butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group; (substituted) aralkyloxycarbonyl groups, e.g., a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl group; (substituted) acyl groups, e.g., an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyl group, and a benzoyl group; (substituted) alkyl groups or (substituted) aralkyl groups, e.g., a t-butyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, and a triphenylmethyl group; (substituted) ether groups, e.g, a methoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group, and a 2,2,2-trichloroethoxymethyl group; and (alkyl- and/or aralkyl)-substituted silyl groups, e.g., a trimethylsilyl group, an isopropyldimethylsilyl group, a t-butyldimethylsilyl group, a tribenzylsilyl group, and a t-butyldiphenylsilyl group.
The resulting compound in which Y or Y1 is an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or a phenylalkyl group composed of an alkylene group having 1 to 6 carbon atoms and a phenyl group can be converted to the corresponding carboxylic acid by treating under an acidic or basic condition commonly used for hydrolysis of carboxylic acid esters.
Where Y1 is the structure of formula (IV), the compound obtained by the reaction between the compound (III) or the compound (V) and the compound (VI) can be converted to the corresponding carboxylic acid by treating under an acidic or basic condition.
When removal of a protective group is necessary, the protective group is removed under the condition properly selected for that protective group to give a desired compound represented by formula (I).
The compound of formula (VI) can be prepared by various processes. A preferred process is shown in Reference Examples hereinafter given, but the process is not limited thereto. The compound of formula (VI) is prepared by removing Qxe2x80x2 from a compound represented by formula: 
wherein R111 is the same as R1 as defined in formula (I) or represents a protective group for amino group; R2, R3, R4, R5, R6, R7, X1, and n are as defined in formula (I); and Qxe2x80x2 is a protective group for amino group, which can be selected from the group consisting of a (substituted) alkoxycarbonyl group, a (substituted) aralkyloxycarbonyl group, a (substituted) acyl group, a (substituted) alkyl group, a (substituted) aralkyl group, and a silyl group.
The above compound can exist in the form of a salt, ahydrate, or a hydrate of the salt. Acid addition salts include inorganic acid salts and organic acid salts. Examples of the inorganic acid salts are a hydrochloride, a sulfate, a nitrate, a hydrobromide, a hydroiodide, and a phosphate. Examples of the organic acid salts include sulfonates, such as a metanesulfonate, a benzenesulfonate, and a toluenesulfonate, and carboxylates, such as an acetate, a citrate, a maleate, a fumarate, and a lactate.
Where both R111 and Qxe2x80x2 represent a protective group for amino group, while they may be the same or different, it is advantageous for the preparation of the compound (I) that these protective groups are different so that they are released under the respective different reaction conditions.
The protective group for amino group as R111 and Qxe2x80x2 includes (substituted) alkoxycarbonyl groups, (substituted) aralkyloxycarbonyl groups, (substituted) acyl groups, (substituted) alkyl groups, (substituted) aralkyl groups, andsilyl groups. Specific examples are (substituted) alkoxycarbonyl groups, e.g., a t-butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group; (substituted) aralkyloxycarbonyl groups, e.g., a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl group; (substituted) acyl groups, e.g., an acetyl group, a methoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, a formyl group, and a benzoyl group; (substituted) alkyl groups or (substituted) aralkyl groups, e.g., a t-butyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzyl group, and a triphenylmethyl group; ether groups, e.g, a methoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group, and a 2,2,2-trichloroethoxymethyl group; and substituted silyl groups, e.g., a trimethylsilyl group, an isopropyldimethylsilyl group, a t-butyldimethylsilyl group, a tribenzylsilyl group, and a t-butyldiphenylsilyl group.
In order to prepare the compound (I) by using the above-described compound having the protective group Qxe2x80x2, it is necessary to remove the protective group Qxe2x80x2 before reacting. In this case, the compound (VI) as obtained may be either subjected to the reaction with the compound (III) or (V) immediately after the protective group removal, usually in the same pot, or once isolated and then reacted.
Cis-2-fluorocyclopropylamine comprising a pure isomer, which is preferred for the synthesis of the compound of formula (I) comprising a pure isomer, can be synthesized by, for example, the process described in JP-A-2-231475. Synthesis of the compound of formula (I) comprising a pure isomer from the optically active cis-2-fluorocyclopropylamine derivative thus obtained can be carried out by, for example, the process described in JP-A-2-231475.
Examples of the compounds of the present invention are shown below.
10-{(1R,2R,6S)-1-Amino-4-azatricyclo[6.1.0.02,6]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylic acid,
8-amino-10-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.02,6]nonan-4-yl}-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1.2.3-de][1,4]benzoxazine-6-carboxylic acid,
5-amino-7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.02,6]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
5-amino-7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.02,6]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.02,6]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.02,6]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid,
7-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.02,6]nonan-4-yl}-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-4-oxo-1,8-naphthridine-3-carboxylic acid,
8-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.02,6]nonan-4-yl}-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid, and
10-{(1R,2R,6S)-1-amino-4-azatricyclo[6.1.0.02,6]nonan-4-yl}-9-fluoro-3-(S)-methyl-2H,3H,6H-oxopyrano[2,3,4-IJ]quinolizine-5-carboxlic acid.
The structures of these specific compounds are shown below. 
The compounds of the present invention have potent antimicrobial activity and are therefore useful as drugs for humans, animals or fishes, agricultural chemicals, or food preservatives.
For use as drugs for humans, the dose of the compound is in the range of from 50 mg to 1 g, preferably from 100 mg to 300 mg, per day for an adult.
For veterinary use, the dose is generally in the range of from 1 to 200 mg, preferably from 5 to 100 mg, per kg of body weight per day while varying depending on the purpose of administration (for therapy or for prevention), the kind and size of the animal, the kind of the pathogenic bacterium and the severity of infection.
The above-mentioned daily dose is given once a day or in 2 to 4 divided doses per day. If necessary, a daily dose may exceed the above-specified upper limit.
The compounds according to the invention are active on a broad range of microorganisms causing various infectious diseases and effective to prevent, alleviate or cure diseases caused by these pathogens.
Examples of bacteria or bacterium-like microorganisms on which the compounds of the invention are effective include Staphylococcus, Streptococcus pyogenes, hemolytic streptococcus, Enterococcus, Streptococcus pneumoniae, peptostreptococcus, gonococcus, Escherichia coli, Citrobacter, Shigella, Klebsiella pneumoniae, Enterobacter, Serratia, Proteus, Pseudomonas aeruginosa, Haemophilus influenzae, Acinetobacter, Campylobacter, and Chlamydozoon trachomatis. 
Diseases which are caused by these pathogens include folliculitis, furuncle, carbuncle, erysipelas, phlegmon, lymphangitis/lymphadenitis, felon, subcutaneous abscess, spiradenitis, acne agminate, infectious atheroma, perianal abscess, mastadenitis, superficial secondary infections after trauma, burn or surgery trauma, pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, secondary infections of chronic respiratory diseases, pneumonia, pyelonephritis, cystitis, prostatitis, epididymitis, gonococcal urethritis, non-gonococcal urethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis, adnexitis, intrauterine infections, bartholinitis, blepharitis, hordeolum, dacryocystitis, tarsadenitis, keratohelcosis, otitis media, sinusitis, paradentosis, pericoronitis, gnathitis, peritonitis, endocarditis, septicemia, meningitis, and skin infections.
The compounds of the invention are also effective on various microorganisms causing veterinary infectious diseases, such as those belonging to the genera Escherichia, Salmonella, Pasteurella, Haemophilus, Bordetella, Staphylococcus, and Mycoplasma. Illustrative examples of the diseases include those of fowl, such as colibacillosis, pullorum disease, avian paratyphosis, fowl cholera, infectious coryza, staphylomycosis, and mycoplasmosis; those of pigs, such as colibacillosis, salmonellosis, pasteurellosis, hemophilus infections, atrophic rhinitis, exudative epidermitis, and mycoplasmosis; those of cattle, such as colibacillosis, salmonellosis, hemorrhagic septicemia, mycoplasmosis, bovine contagious pleuropneumonia, and bovine mastitis; those of dogs, such as colisepsis, salmonellosis, hemorrhagic septicemia, pyometra, and cystitis; those of cats, such as exudative pleurisy, cystitis, chronic rhinitis, and hemophilus infections; and those of kittens, such as bacterial diarrhea and mycoplasmosis.
Dosage forms of antimicrobial preparations containing the compound of the present invention are appropriately selected according to the administration route and can be prepared by conventional preparation methods. Examples of dosage forms for oral administration include tablets, powders, granules, capsules, solutions, syrups, elixirs, and oily or aqueous suspensions.
Injectable preparations may contain adjuvants, such as stabilizers, antiseptics, and solubilizers. The injectable solution which may contain these adjuvants may be put into a container and solidified by, for example, lyophilization to prepare a solid preparation, which is dissolved on use. The container may contain either a single dose or multiple doses.
Preparations for external application include solutions, suspensions, emulsions, ointments, gels, creams, lotions, and sprays.
Solid preparations may contain, in addition to the active compound, pharmaceutically acceptable additives. For example, the active compound is mixed with additives selected according to necessity from among fillers, extenders, binders, disintegrators, absorption accelerators, wetting agents, and lubricants and formulated into solid preparations.
Liquid preparations include solutions, suspensions, and emulsions. They may contain adjuvants, such as suspending agents, emulsifiers, and so forth.
The compound can be administered to animals orally either directly or by mixing into feedstuff, or in a dissolved form directly given to animals or by mixing into water or feedstuff or non-orally by injection.
For veterinary use, the compound can be formulated into powders, fine granules, soluble powders, syrups, solutions, and injections according to the customary methods in the art.
Formulation Examples are shown below.